Potential Role of Stellate Cells in the Regulation of Sinusoidal Tone in Normal Liver

Hepatic stellate cells (HSC) are located in the space of Disse in close contact with hepatocytes and sinusoidal endothelial cells. In human liver, HSC are located along the sinusoids with a nucleus-to-nucleus distance of 40 μm, indicating that the sinusoids are equipped with HSC at certain fixed distances1. These observations suggest that, although the total number of HSC constitutes a small percentage of the total number of liver cells (approximately 5-8%), their spatial disposition and spatial extension may be sufficient to cover the entire hepatic sinusoidal microcirculatory network. The most conspicuous ultrastructural feature of HSC in normal adult liver is the presence of cytoplasmic lipid droplets ranging in diameter from 1-2 μm (i.e., «fat-storing cells» or «lipocytes»)1. These lipid droplets are important in the hepatic storage of retinyl esters, and, accordingly HSC have been shown to play a key role in the metabolism of retinoids. The role of HSC in the progression of liver fibrosis has been extensively characterized. As a consequence of chronic liver tissue damage, HSC, as well as other extracellular matrix-producing cells (e.g. fibroblasts and myofibroblasts constitutively present in the portal tract), undergo a process of activation that leads to a phenotype characterized by increased proliferative, motile and contractile properties. The recognition that HSC have contractile properties represents a key acquisition in the knowledge of the biology of this cell type (see2 for review). Contraction of activated HSC occurs in vitro in response to different vasoconstrictors (table I). However, these findings are likely to be more representative of HSC contractile status in fibrotic liver, where contraction of activated HSC in response to various stimuli may have important implications in the pathogenesis of portal hypertension and in the contraction of mature scar tissue. Following two studies published in 19923, 4 demonstrating the contraction of HSC in response to different vasoconstrictors, the potential involvement of this cell type in the genesis and progression of portal hypertension has reached a level of potential misunderstanding. For this reason, it is necessary to review this issue and reach clear-cut conclusions. In order to proceed in a rational fashion, this paper will address three specific issues: 1. Do HSC play a role in the regulation of sinusoidal tone in the normal liver? 2. Do HSC influence portal pressure in conditions of developing fibrosis and «capillarization» of sinusoids? 3. Do HSC influence portal pressure in the cirrhotic liver?